Project 3: Translational Nanosystems for Improved Lung Cancer Treatment with Small Molecules Non-small cell lung cancer (NSCLC) kills more patients than the next three highest cancers combined. Approximately 70% of the patients are not diagnosed until stage IV metastatic disease where the prognosis is very poor. The standard-of-care with a platinum drug and Taxol only extends life minimally due to many factors including formulation limitations, resistance, poor treatment of metastases, and drug related toxicities. Project 3 takes a translational pipeline approach, using an excellent orthotopic mouse model of metastatic NSCLC to, for the first time, directiy compare three distinct nanoparticle (NP) approaches to deliver otherwise effective small molecule chemotherapies. The unique chemistry, composition, drug release characteristics, formulation and surfaces of the three NPs will optimized and then tested in sensitive and resistant NSCLC cells. Developed drug NPs containing either cisplatin or paditaxel, meeting defined performance and safety criteria, will be screened in an established orthotopic NSCLC model that is metastatic and either sensitive or resistant. In parallel, NPs will be targeted to tumor cells using unique epidermal growth factor receptor (EGFR) recognition ligands developed in the Targeting Ligand Core. Sophisticated pharmacokinetics and direct measurement of in-vivo drug delivery will be performed In collaboration with the PK/PD Core. In-vivo efficacy of drug NPs will be followed with luminescence detection of the luciferase containing lung cancer cells in the orthotopic model in partnership with the Animal Studies Core and the Small Animal Imaging Core. Positive results will be confirmed by CT/PET scanning. The strength of the project is its project management approach and the comparison of three core nanotechnology platforms developed and tested In our current CCNE;1) BTM - a highly scalable oil-core nanocapsule approach with unique activity in multidrug resistant expressing cells and mouse models, 2) PRINT - a 'top-down'fabrication technique to engineer a shape and size specific delivery system with high packaging efficiency and fiexible surface chemistry, and 3) PSQ - a unique inorganic/organic hybrid technology that packages platinum agents in nanoparticles that are targetable and have very favorable drug release capabilities. Successful results in the orthotopic models will be followed by development ofthe drug NP product for eariy phase human trials using UNC-Chapel Hill, NCI NCL/RAID and/or start-up company support. The University Cancer Research Fund (UCRF) has committed $1 million to accelerate selected drug NP product testing in IND enabling studies